ABSTRACT
Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.
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ACKNOWLEDGMENTS
Support from the National Multiple Sclerosis Society (RG4836-A-5) to the Ramanathan laboratory is gratefully acknowledged.
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Author Contributions
Kelly Fellows – Conducted experiments, data analysis, manuscript preparation.
Sheril Alexander, Alyssa Droopad, Jenna Covelli, Vivian Rodriguez-Cruz – Data acquisition.
Murali Ramanathan – Study concept and design, data analysis, manuscript preparation.
Disclosure
Dr. Murali Ramanathan received research funding from the National Multiple Sclerosis Society and the Department of Defense. He received compensation for serving as an Editor from the American Association of Pharmaceutical Scientists. These are unrelated to the research presented in this report.
Kelly Fellows, Sheril Alexander, Alyssa Droopad, Jenna Covelli and Vivian Rodriguez-Cruz have no conflicts to disclose.
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Fellows, K., Rodriguez-Cruz, V., Covelli, J. et al. A Hybrid Markov Chain–von Mises Density Model for the Drug-Dosing Interval and Drug Holiday Distributions. AAPS J 17, 427–437 (2015). https://doi.org/10.1208/s12248-014-9713-5
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DOI: https://doi.org/10.1208/s12248-014-9713-5